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AGS 인체 위암세포에서 DR5의 발현 및 ROS 생성의 증가를 통한 sanguinarine과 TRAIL 혼합처리의 apoptosis 유도 활성 촉진
이택주(Taek Ju Lee),임용균(Im Yong Gyun),최우영(Woo Young Choi),최성현(Sung Hyun Choi),황원덕(Won Deok Hwang),최영현(Yung Hyun Choi) 한국생명과학회 2014 생명과학회지 Vol.24 No.9
혈근초(Sanguinaria canadensis) 뿌리에서 유래된 benzophenanthridine alkaloid의 일종인 sanguinarine은 항균, 항산화 및 항암작용 등 다양한 생리활성을 지니고 있는 것으로 알려져 있다. 비록 TRAIL이 암세포에서는 apoptosis를 유도하지만 정상세포에서는 세포독성을 나타내지 않는다는 큰 장점으로 제 2 임상 단계에서 유의적인 성과를 이루었지만, TRAIL 저항성을 극복해야 하는 큰 어려움이 남아있다. 본 연구실에서는TRAIL이 세포독성을 나타내지 않는 범위의 sanguinarine과 혼합처리에 의하여 TRAIL 저항성 AGS 위암세포에서 apoptosis를 유발하였음을 보고한 바 있으며, 본 연구에서는 sanguinarine의 TRAIL 저항성 관련 극복에 대한 추가적인 기전 연구를 실시하였다. 본 연구의 결과에 의하면, sanguinarine과 TRAIL의 혼합처리는 각각의 단독 처리에 비하여 AGS 세포의 증식억제 및 apoptosis 유도의 상승 효과가 있었으며, 이를 MTT assay, agarode gel 전기영동, 염색질 응축 현상 및 flow cytometry 분석을 통하여 확인하였다. 또한 sanguinarine과 TRAIL의 혼합처리는 DR5의 발현을 증가시켰으며, ROS의 생성을 촉진시켰다. 그러나 동일 조건에서 MAPKs 신호 전달계에는 큰 영향을 주지 않았다. 아울러 ROS 생성을 인위적으로 차단하였을 경우, sanguinarine과 TRAIL의 혼합처리에 의한 생존도 저하가 유의적으로 회복되었다. 이러한 결과는 sanguinarine과 TRAIL이 DR5의 발현 증가와 ROS의 생성을 촉진시킴으로서 apoptosis 신호를 활성화하였음을 의미하는 결과로서 TRAIL 저항성 극복을 위한 sanguinarine 활용의 유용성을 보여주는 것이다. Sanguinarine, a benzophenanthridine alkaloid originally derived from the root of Sanguinaria canadensis, has been shown to possess antimicrobial, antioxidant, and anti-cancer properties. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells, but not most normal cells and has shown efficacy in a phase 2 clinical trial, development of resistance to TRAIL by tumor cells is a major roadblock. Our previous study indicated that treatment with TRAIL in combination with subtoxic concentrations of sanguinarine sensitized TRAIL-mediated apoptosis in TRAIL-resistant human gastric carcinoma AGS cells; however, the detailed mechanisms are not fully understood. In this study, we show that sanguinarine sensitizes AGS cells to TRAILmediated apoptosis as detected by MTT assay, agarose gel electrophoresis, chromatin condensation and flow cytometry analysis. Combined treatment with sanguinarine and TRAIL effectively induced expression of death receptor (DR) 5 but did not affect expression of DR4 and mitogen activated protein kinases signaling molecules. Moreover, the combined treatment with sanguinarine and TRAIL increased the generation of reactive oxygen species (ROS); however, N-acetylcysteine, ROS scavenger, significantly recovered growth inhibition induced by the combined treatment. Taken together, our results indicate that sanguinarine can potentiate TRAIL-mediated apoptosis through up-regulation of DR5 expression and ROS generation.
Choi, Bong-In,Kwak, Yeong-Don,Jung, Yu-Mi,Ryu, Byung-Taek,Kim, Chang Gyun The Korean Society of Environmental Toxicology 2015 환경독성보건학회지 Vol.30 No.-
Objectives Approximately 2000 phase-in substances are subject to registration according to the Act on the Registration and Evaluation, etc. of Chemical Substances (K-REACH), and the expected testing cost is 2.06 trillion Korean won assuming all the test data required for registration are acquired. The extent to which these enormous test costs can be reduced depends on the availability of existing data that can be used to meet the requirements of the K-REACH we examined the current availability of test data that can be used for chemical substance registration. Methods We analyzed the possibility of utilizing the existing test data obtained from 16 reference databases for 369 of 518 kinds of phase-in substances subject to registration that were reported in last October 2014. Results The physical and chemical properties were available for 57.1% of substances, whereas data regarding human hazards and environmental hazards were available at considerably lower rates, 8.5% and 11.8%, respectively. Conclusions Physical and chemical properties were available for a fairly high proportion, whereas human hazards and environmental hazards were reported for considerably fewer substances.
지속성 외래 복막투석 환자에서 발생한 당뇨병성 근육 경색증
정택균 ( Taek Kyun Jeong ),이연경 ( Youn Kyoung Lee ),정균호 ( Gyun Ho Jeong ),박병석 ( Byong Seok Park ),마성권 ( Seong Kwon Ma ),김수완 ( Soo Wan Kim ),김남호 ( Nam Ho Kim ),최기철 ( Ki Chul Choi ) 대한신장학회 2003 Kidney Research and Clinical Practice Vol.22 No.1
Diabetic muscle infarction (DMI) is a rare condition occurring in subjects with long-standing complicated diabetes mellitus. We report DMI in a 65-vear-old man with type 2 diabetes mellitus undergoing continous ambulatory peritoneal dialysis (CAPD) with review of this condition in the literature. He had been suffered from type 2 diabetes mellitus for 21 years. In 1997, he reached end-stage renal disease and had received on renal replacement therapy with CAPD since then. In June 2002, he presented with sudden and spontaneous onset of severe pain in the right thigh region. He was afebrile, and the right thigh was swollen and tender but not erythematous. Laboratory data on admission included white blood cell count of 15,800/㎣, hemoglobin 9.0g/dL, platelet count 264,000/㎣, BUN 102.3mg/dL, serum creatinine 9.9 mg/dL, fasting blood glucose 85 mg/dL, postprandial 2 hours blood glucose 162 mg/dL, hemoglobin AIC 5.84%, ESR 125 mm/h (it was 52 mm/h one month earilier), CRP 18.9 mg/dL, and normal levels of creatinine kinase. Magnetic resonance imaging (MRI) showed asymmetry of the muscle in T1-weighted images and increased signal intensity involving the medial portion of right thigh (adductor longus, adductor magnus, vastus intermedius muscle, etc) in T2-weighted images with no contrast enhancement. Radioistope venography of the ileo-femoral veins was was normal, excluding deep venous thrombosis as a cause. The right thigh was explored surgically and a biopsy taken from the vastus intermedius muscle was consistent with chronically inflammed scar tissue with no evidence of malignancy. A biopsy taken from the vastus intermedius muscle showed hemorrhagic necrosis of skeletal muscle, with lymphcytic infiltration. Most of the blood vessels appeared normal. The swelling resolved spontaneously following a few weeks of bedrest and analgesia. To our knowledge, this is the first reported case of DMI in patients undergoing renal replacement therapy in Korea.
Aluminum Nanoparticles Induce ERK and p38MAPK Activation in Rat Brain
Jung-Taek Kwon,Gyun-Baek Seo,Eunhye Jo,Mimi Lee,Hyun-Mi Kim,Ilseob Shim,Byung-Woo Lee,Byung-Il Yoon,Pilje Kim,Kyunghee Choi 한국독성학회 2013 Toxicological Research Vol.29 No.3
Aluminum nanoparticles (Al-NPs) are one of the most widely used nanomaterial in cosmetics and medical materials. For this reason, Al-NP exposure is very likely to occur via inhalation in the environment and the workplace. Nevertheless, little is known about the mechanism of Al-NP neurotoxicity via inhalation exposure. In this study, we investigated the effect AL-NPs on the brain. Rats were exposed to Al-NPs by nasal instillation at 1 mg/kg body weight (low exposure group), 20 mg/kg body weight (moderate exposure group), and 40 mg/kg body weight (high exposure group), for a total of 3 times, with a 24-hr interval after each exposure. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated that the presence of aluminum was increased in a dose-dependent manner in the olfactory bulb (OFB) and the brain. In microarray analysis, the regulation of mitogen-activated protein kinases (MAPK) activity (GO: 0043405), including Ptprc, P2rx7, Map2k4, Trib3, Trib1, and Fgd4 was significantly over-expressed in the treated mice than in the controls (p = 0.0027). Moreover, Al-NPs induced the activation of ERK1 and p38 MAPK protein expression in the brain, but did not alter the protein expression of JNK, when compared to the control. These data demonstrate that the nasal exposure of Al-NPs can permeate the brain via the olfactory bulb and modulate the gene and protein expression of MAPK and its activity.
( Noorie Choi ),( Chang Geol Lee ),( Yong Chan Ahn ),( Dongryul Oh ),( Sang Wook Lee ),( Hong Gyun Wu ),( Sung Ho Moon ),( Yeon Sil Kim ),( Young Taek Oh ),( O Kyu Noh ),( Jin Ho Kim ) 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1
Background: Outcomes of postoperative radiotherapy(PORT) for squamous cell carcinoma of the tonsil were analyzed focusing on management and control of the neck.Methods: Medical records of 380 pathologically-confirmed tonsil cancer patients, treated with surgery and PORT from February 1993 to January 2011 at 15 institutions, were reviewed. Neck metastasis was absent(pN0) in 53(13.9%) and present(pN+) in 327(86.1%), of which 279(85.3%), 2(0.6%), and 46(14.1%) were ipsilateral, contralateral, and bilateral, respectively. Results: Neck irradiation(NI) was done in 346(91.1%) patients, while data was unavailable in 34(8.9%). After a median follow-up of 53 months, neck recurrence occurred in 28(7.4%) patients. Among the 53 pN0 patients, NI was ipsilateral-only, bilateral, and unknown in 25(47.2%), 21(39.6%), and 7(13.2%). One patient suffered from contralateral neck failure after an ipsilateral-only NI. For the 279 ipsilateral pN+ patients, NI was ipsilateral-only, bilateral, and unknown in 67(24.0%), 193(69.2%), and 19(6.8%). Neck recurrence occurred in 18(6.5%): 11(3.9%), 6(2.2%) and 1(0.4%) failed in the ipsilateral-only, contralateral-only, and bilateral neck. The 2 contralateral pN+ patients received bilateral NI and remained free of regional recurrence. NI data was available for 38(82.6%) of the 46 bilateral pN+ patients and all received bilateral NI. Three(6.5%), 2(4.3%) and 2(4.3%) patients recurred in the ipsilateral, contralateral, and bilateral neck. Conclusions: Because contralateral neck failure is rare in pN0 patients, elective NI may safely be confi ned to the ipsilateral neck-only. For pN+ patients, however, the risk of contralateral neck failure highly varies (3 to 10%). Thus clinicopathologic factors should be considered to justify the omission of contralateral NI for such heterogenous groups.
Tae Gyun Kim,Taek Hun Kwon,Hyojeong Choi,Min-Kyung Park,JoongBae Park,In Gyeong Chae,Hyun-Jung An 한국구조생물학회 2022 Biodesign Vol.10 No.4
Pyridine-2,3-dicarboxylic acid which is a biologically potent molecule implicated in the neurodegenerative environment is catalyzed by nicotinate-nucleotide pyrophosphorylase (NMnPP) to produce a precursor molecule, nicotinate mononucleotide (NMn), of de novo biosynthesis of the coenzyme nicotinamide adenine dinucleotide (NAD+). The protein preparation, crystallization, and preliminary structural features of full-length enzyme in complex with product reactant suggest that yeast NMnPP acts as stable hexamer formation. Crystals of S. cerevisiae NMnPP were obtained and diffracted to a resolution of 1.74 Å and 1.99 Å for apo and complex forms, belonged to the trigonal symmetry group R32 in the unit-cell parameters of a = b = 155.313, c = 67.507 and a = b = 155.091, c = 69.204, respectively. Based on our comparison of eukaryotic NMnPP structures in the apo and complex forms, we propose functional and structural investigation for product binding and hexamer stabilization.